Epilepsy is a leading neurological disorder. One to four million Americans and twenty to forty million people world-wide suffer from some form of epilepsy, making it second only to stroke as the leading neurological disorder. Although standard therapy permits control of seizures in 80% of these patients, one-half million people in the U.S. have uncontrolled epilepsy. The number of drugs useful for the treatment of epilepsy is remarkably small. Fewer than 20 drugs are currently marketed in the U.S., and of these, only five or six are widely used. Complex partial epilepsy (also known as temporal lobe, psychomotor or limbic epilepsy), the most devastating form among adults, and estimated to account for as many as two-thirds of all cases, is refractory to drug treatment [Gummit, R. J., "The Epilepsy Handbook, The Practical Management of Seizures", Raven Press, New York, 1983]. It is becoming increasingly evident that significant progress toward complete control can be achieved only by an understanding of the mechanisms of the epilepsies themselves, which will provide the molecular basis for antiepileptic drug design and development, and new treatment strategies.
NMDA (N-methyl-D-aspartate) receptor overstimulation by high levels of the excitatory amino acid (EAA), L-glutamate, has been implicated in epileptogenesis and epilepsy [Cavalheiro, et al., "Frontiers in Excitatory Amino Acid Research", A. R. Liss, New York, 1988]. Thus, development of agents that are EAA/NMDA antagonists may constitute novel and effective therapies for the epilepsies. Although a number of EAA inhibitors has been discovered, many lack NMDA receptor specificity and are too toxic for clinical studies [Porter, Epilepsia, 30 S29-34, 1989].
Thus, the successful optical resolution of several racemic AAPs and the discovery of this invention of the (+) enantiomers of the AAPs as a superior, more potent class of anticonvulsant agents in the Applicant's laboratories are significant. The (+) AAP enantiomers of this invention, derived from the optical resolution of the corresponding racemic mixtures of anticonvulsant AAP compounds (Kadaba, P. K, U.S. Pat. No. 5,648,369, Jul. 15, 1997), are highly potent, orally effective, 20 nonneurotoxic EAA antagonists with very high therapeutic or protective index values (TD.sub.50 /ED.sub.50, the ratio of toxic dose in 50% of the animals to the effective dose in 50% of the animals) better than that of the racemic AAPs, and hold promise for commercial development as nontoxic, clinically useful antiepileptic drugs for the management of epilepsy in humans.